MIGRANADE, INC. pursuing an agreement with the UNITED STATES ARMED FORCES for inclusion of MIGRANADE Migraine Relief as an issuance to all active military personnel.

Dr. Charles B. Hensley's discovery of the cause and propagation of migraine headaches

RAPID COMMUNICATION

A PROPOSED ROLE FOR ACUTELY DIMINISHED LEVELS OF INTRACELLULAR REDUCED GLUTATHIONE (GSH) IN THE GENESIS AND PROPRAGATION OF MIGRAINE HEADACHES

Charles B. Hensley, Ph.D.

Los Angeles, California

Migraine headache is a common disorder afflicting an estimated 36 million people (12% of the general population) in the United States (1) and over 1 billion people worldwide. The estimated annual costs for the United States alone totals in excess of 17 billion dollars, which includes costs of medications; office, clinic, or emergency department visits; laboratory and diagnostic services; management of treatment side effects and lost productivity in the workplace (2).

According to the World Health Organization, migraine headaches are a major cause of disability worldwide, imposing burdens that include substantial personal suffering, reduced quality of life. Repeated headache attacks, and often fear of future attacks, damage family life, social life, and employment (3). Migraines are more prevalent in women with one out of every six women reporting experiencing migraines and the incidence of migraines is thought to be under-reported due to the social stigma associated with migraines. There is also evidence suggesting athletes and military personnel are at increased risk of migraine after suffering head injuries.

The current OTC medications used for treating migraines include ibuprofen (Advil, Motrin, others) or acetaminophen (Tylenol, others) and combination drugs such as Excedrin Migraine. These medications are not effective for severe migraines and if taken too often or for long periods of time, these medications can lead to ulcers, gastrointestinal bleeding and rebound headaches (4).

Prescription medications include sumatriptan (Imitrex), rizatriptan (Maxalt), almotriptan (Axert), naratriptan (Amerge), zolmitriptan (Zomig), frovatriptan (Frova) and eletriptan (Relpax). These medications are expensive, are not always effective, are slow to act, and have serious side effects. Side effects include nausea, dizziness and muscle weakness and they aren't recommended for people at risk for strokes and heart attacks.

It is my contention that the underlying reason that prescriptive and over-the-counter medications for migraine headache have limited efficacy and cause undesirable side effects is due in large part to a general lack of understanding of the etiology of the disease.

In this paper, I put forth a novel hypothesis for the primary cause of migraines and a treatment rationale. The basis of my hypothesis is the fact that excitatory amino acid transporter (EAAT)-mediated cysteine transport via the cysteine/glutamate anti-porter is the mechanism used by neurons to obtain cysteine for the synthesis of reduced glutathione (GSH), a key molecule in preventing oxidative stress and neuronal toxicity. A key feature of my hypothesis is the observation that disruptions in glutathione homeostasis and alterations in glutathione-dependent enzyme activities appear to be associated with the induction and progression of several neurodegenerative diseases (5).

These transporters mediate cysteine entry in exchange for intracellular glutamate and conditions impacting this transporter affect the transport of cysteine into cells (6, 7). Maintaining sufficient intracellular concentrations of cysteine is critical not only for protein synthesis but also for maintenance of cellular redox homeostasis as cysteine is the rate limiting component for the synthesis of GSH, a critical co-factor of the intracellular antioxidant machinery (6, 7). Furthermore, low intracellular GSH leads to disruption of normal mitochondrial function (8) which impacts neuronal cellular energetics, a condition that has been linked to migraine headaches (9).

I hypothesize that migraine headaches are in part, a consequence of a deficit in neuronal intracellular reduced glutathione levels and that acute or chronic inhibition in the transport of cysteine via the EAAT transport system may be a primary event in the initiation and propagation of migraine headaches. I further hypothesize that exogenously supplied GSH directly to the trigeminal nerve and subsequently to the central nervous system via the trigeminal nerve pathway could restore the neuronal GSH by circumventing the EAAT transport system.

Unfortunately, supplying GSH exogenously to the CNS is problematic due to the extremely low bioavailability of oral GSH formulations and chemical instability of GSH nasal sprays or other liquid GSH formulations. To overcome these obstacles, I developed an orally delivered formulation containing GSH in a proprietary effervescing delivery system designed to transport directly GSH to the CNS via the trigeminal nerves.

To test this hypothesis, I developed a formulation containing GSH in a proprietary effervescing liquid delivery system. Administration of the formulation to human subjects experiencing moderate to severe migraine headaches proved to be highly effective in 100% of the subjects without any observable side effects with maximum relief occurring in 12.6 ± 6 minutes (n = 50) (Submitted for publication). These results support my hypothesis and demonstrate that GSH supplied orally via a proprietary effervescing delivery system, can resists degradation and cross the blood brain barrier intact, thereby restoring neuronal intracellular levels of GSH relevant to the genesis and propagation of migraine headaches.

10. Smitherman TA, Burch R, Sheikh H, Loder E. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache. (2013) Mar;53(3):427-36.